Phenylacetic Acid Derivatives

ABSTRACT

Compounds of formula (I) pharmaceutically acceptable salts thereof, and pharmaceutically acceptable esters thereof; which are useful for the treatment of COX-2 dependent disorders.

The invention relates to phenylacetic acids and derivatives as definedherein which are particularly potent and selective cyclooxygenase-2(COX-2) inhibitors, methods for preparation thereof, pharmaceuticalcompositions comprising said compounds, methods of selectivelyinhibiting COX-2 activity and of treating conditions in mammals whichare responsive to COX-2 inhibition using said compounds orpharmaceutical compositions comprising said compounds of the invention.

The present invention provides novel phenylacetic acids and derivativeswhich inhibit COX-2 without significantly inhibiting cyclooxygenase-1(COX-1). The invention thus provides novel non-steroidalanti-inflammatory agents which are surprisingly free of undesirable sideeffects usually associated with the classical non-steroidalanti-inflammatory agents, such as gastrointestinal and renal sideeffects.

The compounds of the present invention are thus particularly useful ormay be metabolically converted to compounds which are particularlyuseful as selective COX-2 inhibitors. They are thus particularly usefulfor the treatment of COX-2 dependent disorders in mammals, includinginflammation, pyresis, pain, osteoarthritis, rheumatoid arthritis,dysmenorrhea, migraine headache, cancer (such as of the digestive tract,e.g., colon cancer and melanoma), cancer pain, acute pain, chronic pain,neurodegenerative diseases (such as multiple sclerosis, Parkinson'sdisease and Alzheimer's disease), cardiovascular disorders (such asatherosclerosis, coronary artery disease and arteriosclerosis),osteoporosis, gout, acute gout, asthma, lupus and psoriasis whilesubstantially eliminating undesirable gastrointestinal ulcerationassociated with conventional cyclooxygenase (COX) inhibitors. Thecompounds of the invention are also UV absorbers, in particular, UV-Babsorbers, and are useful for blocking or absorbing UV radiation, forinstance, for the treatment and prevention of sunburn, e.g., in suntanproducts.

Ocular applications of the compounds of the invention include thetreatment of ocular inflammation, wet age-related macular degeneration,ocular pain including pain associated with ocular surgery, such as PRKor cataract surgery, of ocular allergy, of photophobia of variousetiology, of elevated intraocular pressure (in glaucoma) by inhibitingthe production of trabecular meshwork inducible glucocorticoid responseprotein and of dry eye disease.

The compounds of the present invention are useful for the treatment ofneoplasia particularly neoplasia that produce prostaglandins or expressCOX, including both benign and cancerous tumors, growths and polyps, inparticular, epithelium cell-derived neoplasia. Compounds of the presentinvention are, in particular, useful for the treatment of liver,bladder, pancreatic, ovarian, prostate, cervical, lung and breast cancerand, especially gastrointestinal cancer, e.g., cancer of the colon, andskin cancer, e.g., squamous cell or basal cell cancers and melanoma, asindicated above.

The term “treatment” as used herein is to be understood as includingboth therapeutic and prophylactic modes of therapy, e.g., in relation tothe treatment of neoplasia, therapy to prevent the onset of clinicallyor pre-clinically evident neoplasia, or for the prevention of initiationof malignant cells or to arrest or reverse the progression ofpre-malignant to malignant cells, as well as the prevention orinhibition of neoplasia growth or metastasis. In this context, thepresent invention is, in particular, to be understood as embracing theuse of compounds of the present invention to inhibit or preventdevelopment of skin cancer, e.g., squamous or basal cell carcinomaconsequential to UV light exposure, e.g., resulting from chronicexposure to the sun. The compounds may be used in humans or in othermammals.

In a first aspect of the invention there is provided a compound offormula (I)

whereinR is methyl or ethyl;R₃ is halo or C₁-C₆ alkyl;R₄ is C₁-C₆ alkyl;R₅ is halo;the above mentioned C₁-C₆ alkyl at R₃ and R₄ being optionallysubstituted by one or more halo groups;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable esters thereof.

Preferably in compounds of formula (I), R₃ is halo, methyl or ethyl.More preferably it is halo. Alternatively preferably it is chloro.

Preferably in compounds of formula (I), R₄ is C₁-C₃ alkyl, optionallysubstituted by one or more halo groups. More preferably it is methyl,ethyl, isopropyl or trifluoromethyl. Yet more preferably it is methyl.Alternatively preferably it is trifluoromethyl.

Preferably in compounds of formula (I), R₅ is chloro or fluoro.

Yet more preferably both R₃ and R₅ are independently selected fromchloro and fluoro.

Preferably the compound is selected from the following list ofcompounds:

-   5-methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid-   5-ethyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid-   5-methyl-2-(2′-fluoro-3′-trifluoromethyl-4′-ethylanilino)phenylacetic    acid-   5-ethyl-2-(2′-fluoro-3′-trifluoromethyl-4′-ethylanilino)phenylacetic    acid-   5-methyl-2-(2′-fluoro-3′-trifluoromethyl-4′-methylanilino)phenylacetic    acid-   5-ethyl-2-(2′-fluoro-3′-trifluoromethyl-4′-methylanilino)phenylacetic    acid-   5-methyl-2-(2′-fluoro-3′-methyl-4′chloroanilino)phenylacetic acid-   5-ethyl-2-(2′-fluoro-3′-methyl-4′chloroanilino)phenylacetic acid-   5-methyl-2-(2′-fluoro-3′-ethyl-4′chloroanilino)phenylacetic acid-   5-ethyl-2-(2′-fluoro-3′-ethyl-4′chloroanilino)phenylacetic acid-   5-methyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid-   5-ethyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid-   5-ethyl-2-(2′-fluoro-3′-isopropyl-4′chloroanilino)phenylacetic acid-   5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid    diethylamine salt-   sodium 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate-   5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid    tromethamine salt-   calcium 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate    monohydrate-   Lysine 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate    monohydrate-   choline 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate    monohydrate-   Potassium 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate.

In a second aspect, the invention provides a pharmaceutical compositioncomprising an effective amount of a compound of formula (I) incombination with one or more pharmaceutically acceptable carriers.

In a third aspect, the invention provides a method of treatingcyclooxygenase-2 (COX-2) dependent disorders in mammals which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I).

In a fourth aspect, the invention provides a method of selectivelyinhibiting COX-2 activity in a mammal without substantially inhibitingcyclooxygenase-1 activity which comprises administering to a mammal inneed thereof an effective COX-2 inhibiting amount of a compound offormula (I).

In a fifth aspect, the invention provides a method of treatingrheumatoid arthritis, osteoarthritis, dysmenorrhea, pain, tumors orinflammation in mammals which comprises administering to a mammal inneed thereof a correspondingly effective amount of a compound of formula(I).

In a sixth aspect, the invention provides the use of a compound offormula (I) in the manufacture of a medicament for the treatment ofrheumatoid arthritis, osteoarthritis, dysmenorrhea, pain, tumors orinflammation.

In a seventh aspect, the invention provides a compound of formula (I)for use in the treatment of a COX-2 dependent disorder.

In an eighth aspect, the invention provides a method for the preparationof a compound of formula (I) of claim 1 which comprises the step of:

(a) coupling a compound of formula (II) or (III)

wherein

-   -   Z is bromo or iodo;    -   R has meaning as defined above;    -   R_(a) is hydrogen, an alkali metal cation or lower alkyl,        preferably isopropyl; and    -   R₆ and R₇ are lower alkyl; or R₆ and R₇, together with the        nitrogen atom, represent morpholino, piperidino or pyrrolidino;        with a compound of formula (IV)

wherein R₃-R₅ have meaning as defined above in the presence of copperand cuprous iodide to obtain a compound of formula (V) or (VI)

and hydrolyzing the resulting compound of formula (V) or (VI) to acompound of formula (I); or(b) condensing a compound of formula (VII)

wherein R₃-R₇ have meaning as defined herein, with a reactive functionalderivative of an acid, e.g., acetic acid, such as acetyl chloride, in aFriedel-Crafts acylation to reaction to obtain, e.g., a compound of theformula (VIII)

wherein R₃-R₇ have meaning as defined herein, which is in turnhydrogenolyzed and then hydrolyzed to obtain a compound of formula (I),wherein R represents, e.g., ethyl; or(c) hydrolyzing a lactam of formula (IX)

wherein R and R₃-R₅ have meaning as defined herein, with a strong base;and in above processes, if desired, temporarily protecting anyinterfering reactive groups and then isolating the resulting compound ofthe invention; and, if desired, converting any resulting compound intoanother compound of the invention; and/or if desired converting a freecarboxylic acid of the invention into a pharmaceutically acceptableester derivative thereof; and/or if desired, converting a resulting freeacid into a salt or a resulting salt into the free acid or into anothersalt.

In starting compounds and intermediates, which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, hydroxy and carboxyl groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected hydroxy, amino and carboxylgroups are those that can be converted under mild conditions into freeamino, hydroxy and carboxyl groups without other undesirable sidereactions taking place. For example, hydroxy protecting groups arepreferably benzyl or substituted benzyl groups, or acyl groups, such aspivaloyl.

The preparation of compounds of formulae (V) and (VI) according toprocess (a) is carried out under conditions of a modified Ullmanncondensation for the preparation of diarylamines, e.g., in the presenceof copper powder and copper (I) iodide and potassium carbonate,optionally in an inert high boiling solvent, such as nitrobenzene,toluene, xylene or N-methylpyrrolidone, at elevated temperature, e.g.,in the range of 100-200° C., preferably at reflux temperature, accordingto general methodology described by Nohara, Chem Abstr, Vol. 94, p.15402x (1951); and Moser et al., J Med Chem, Vol. 33, p. 2358 (1990).When Z is bromo, the condensation is carried out in the presence of aniodide salt, e.g., potassium iodide.

Hydrolysis of the resulting ortho-anilinophenylacetamides of formula (V)is carried out in aqueous alkali hydroxide, e.g., in 6 N NaOH in thepresence of an alcohol, e.g., ethanol, propanol and butanol, at elevatedtemperature, such as reflux temperature of the reaction mixture.

The hydrolysis of esters of formula (VI) is carried out according tomethods known in the art, e.g., under basic conditions as describedabove for the compounds of formula (V) or alternatively under acidicconditions, e.g., using methanesulfonic acid.

The starting materials of formula (II) or (III) are generally known orcan be prepared using methodology known in the art, e.g. as described byNohara in Japanese patent application No. 78/96,434 (1978); U.S. Pat.No. 6,291,523 and as illustrated herein.

For example, the corresponding anthranilic acid is converted to theortho-diazonium derivative followed by treatment with an alkali metaliodide in acid, e.g., sulfuric acid, to obtain the 2-iodobenzoic acid orlower alkyl ester thereof. Reduction to the corresponding benzylalcohol, e.g., with diborane or lithium aluminum hydride for the ester,conversion of the alcohol first to the bromide and then to the nitrile,hydrolysis of the nitrile to the acetic acid and conversion to theN,N-dialkylamide according to methodology known in the art yields astarting material of formula (II).

Alternatively, e.g., the starting material of formula (II), wherein Z isBr and R is cyclopropyl can be prepared by first condensing according tothe method outlined in J Am Chem Soc, Vol. 123, p. 4155 (2001), e.g.,2-bromo-5-iodobenzoic acid methyl ester with cyclopropyl bromide in thepresence of indium trichloride to obtain 2-bromo-5-cyclopropylbenzoicacid methyl ester which is converted as described above to thecorresponding 2-bromo-5-cyclopropylphenylacetamide of formula (II).

Furthermore, the starting materials of formula (II), wherein R is, e.g.,ethyl, can be prepared by Friedel-Crafts acetylation of oxindole with,e.g., acetyl chloride in the presence of aluminum chloride, reduction ofthe resulting ketone by, e.g., catalytic hydrogenolysis, followed byhydrolytic cleavage of the resulting 5-ethyloxindole to the orthoamino-phenylacetic acid. Diazotization in the presence of, e.g.,potassium iodide yields the ortho iodo-phenylacetic acid which isconverted to an amide of formula (II).

Esters of formula (III) are prepared from the corresponding acidsaccording to esterification methods known in the art.

The anilines of formula (IV) are either known in the art or are preparedaccording to methods well-known in the art, and as illustrated herein.

The preparation of, e.g., 5-ethyl or 5-n-propyl substituted compoundsaccording to process (b) is carried out under conditions ofFriedel-Crafts acylation, e.g., in the presence of aluminum chloride inan inert solvent, such as 1,2-dichloroethane, followed byhydrogenolysis, e.g., using palladium on charcoal catalyst, preferablyin acetic acid as solvent, at room temperature and about 3 atmospherespressure.

The starting materials of formula (VII) are prepared generally asdescribed under process (a) starting with an amide of formula (II) inwhich R represents hydrogen, e.g., as described in Moser et al. (1990),supra.

The preparation of the compounds of the invention according to process(c) can be carried out under conditions known in the art for thehydrolytic cleavage of lactams, preferably with a strong aqueous base,such as aqueous sodium hydroxide, optionally in the presence of anorganic water miscible solvent, such as methanol at elevated temperaturein the range of about 50-100° C., as generally described in U.S. Pat.No. 3,558,690.

The oxindole starting materials of formula (IX) are prepared byN-acylation of a diarylamine of the formula (X)

wherein R and R₁-R₅ have meaning as defined above, with a haloacetylchloride, preferably chloroacetyl chloride, advantageously at elevatedtemperature, e.g., near 100° C., to obtain a compound of the formula(XI)

wherein R and R₃-R₅ have meaning as defined hereinabove. Cyclization ofa compound of formula (XI) is carried out under conditions ofFriedel-Crafts alkylation in an inert solvent, such as dichlorobenzene,in the presence of Friedel-Crafts catalysts, e.g., aluminum chloride andethylaluminum dichloride, at elevated temperature, e.g., at 120-175° C.

The starting amines of formula (X) can be prepared by an Ullmanncondensation and other methods known in the art, e.g., a Buchwaldcoupling reaction.

Esters of the carboxylic acids of formula (I) are prepared bycondensation of the carboxylic acid, in the form of a salt or in thepresence of a base, with a halide (bromide or chloride) corresponding tothe esterifying alcohol, such as benzyl chloroacetate, according tomethodology well-known in the art, e.g., in a polar solvent, such asN,N-dimethylformamide, and if required further modifying the resultingproduct. For example, if the esteriftcation product is itself an ester,such can be converted to the carboxylic acid, e.g., by hydrogenolysis ofa resulting benzyl ester. Also if the esterification product is itself ahalide, such can for instance be converted to the nitrooxy derivative byreaction with, e.g., silver nitrate.

For example, the compounds of formula (Ia) are preferably prepared bycondensing a salt of a carboxylic acid of formula (I) above with acompound of formula

X—CH₂—COOR_(b)

wherein

X is a leaving group; and

R_(b) is a carboxy-protecting group;

to obtain a compound of formula (Ia) in carboxy-protected form, andsubsequently removing the protecting group R_(b).

The esterification can be carried under esterification conditions knownin the art, e.g., in a polar solvent, such as N,N-dimethylformamide, ata temperature range of room temperature to about 100° C., preferably ata range of 40-60° C., e.g., according to the procedure described in U.S.Pat. No. 5,291,523.

The salt of the acid of formula (I) is preferably an alkali metal salt,e.g., the sodium salt which may be prepared in situ.

Leaving group X is preferably halo, e.g., chloro or bromo, or loweralkylsulfonyloxy, e.g., methanesulfonyloxy.

Carboxy-protecting group R_(b) is preferably benzyl.

The resulting benzyl esters can be converted to the free acids offormula (Ia) preferably by hydrogenolysis with hydrogen in the presenceof, e.g., Pd/C catalyst in acetic acid at atmospheric pressure or underParr hydrogenation at a temperature ranging from room temperature toabout 50° C.

The invention includes any novel starting materials and processes fortheir manufacture.

Finally, compounds of the invention are either obtained in the freeform, or as a salt thereof if salt forming groups are present.

The acidic compounds of the invention may be converted into metal saltswith pharmaceutically acceptable bases, e.g., an aqueous alkali metalhydroxide, advantageously in the presence of an ethereal or alcoholicsolvent, such as a lower alkanol. Resulting salts may be converted intothe free compounds by treatment with acids. These or other salts canalso be used for purification of the compounds obtained. Ammonium saltsare obtained by reaction with the appropriate amine, e.g., diethylamine,and the like.

Compounds of the invention having basic groups can be converted intoacid addition salts, especially pharmaceutically acceptable salts. Theseare formed, e.g., with inorganic acids, such as mineral acids, e.g.,sulfuric acid, a phosphoric or hydrohalic acid; or with organiccarboxylic acids, such as (C₁-C₄)alkanecarboxylic acids which, e.g., areunsubstituted or substituted by halogen, e.g., acetic acid, such assaturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic,maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic,lactic, malic, tartaric or citric acid, such as amino acids, e.g.,aspartic or glutamic acid; or with organic sulfonic acids, such as(C₁-C₄)alkylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonicacids which are unsubstituted or substituted, e.g., by halogen.Preferred are salts formed with hydrochloric acid, methanesulfonic acidand maleic acid.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The general definitions used herein have the following meaning withinthe scope of the present invention, unless otherwise indicated.

Pharmaceutically acceptable esters are preferably prodrug esterderivatives which are convertible by solvolysis or under physiologicalconditions to the free carboxylic acids of, e.g., formula (I). Suchesters are, e.g., lower alkyl esters, such as the methyl or ethyl ester;carboxy-lower alkyl esters, such as the carboxymethyl ester; nitrooxy-or nitrosooxy-lower alkyl esters, such as the 4-nitrooxybutyl or4-nitrosooxybutyl ester; and the like. Preferred are thephenylacetoxyacetic acids of formula (Ia)

wherein R, R₃, R₄ and R₅ have meaning as defined hereinabove forcompounds of formula (I); and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts represent metal salts, such asalkaline metal salts, e.g., sodium, potassium, magnesium or calciumsalts; as well as ammonium salts, which are formed, e.g., with ammoniaand mono- or di-alkylamines, such as diethylammonium salts; and withamino acids, such as arginine and histidine salts.

A lower alkyl group contains up to 6 carbon atoms, preferably 1-4 carbonatoms, may be straight chain or branched and represents, e.g., methyl,ethyl, propyl, butyl, isopropyl, isobutyl and the like, preferablymethyl or ethyl. Lower alkoxy is methoxy, ethoxy and the like.

Halo is preferably chloro, bromo or fluoro, advantageously chloro orfluoro.

The compounds of the invention are useful as selective COX-2 inhibitorsor as prodrugs thereof. The selective COX-2 inhibitors and prodrugsthereof of the invention are particularly useful for the treatment of,e.g., inflammation, pyresis, pain, osteoarthritis, dysmenorrhea,rheumatoid arthritis and other conditions responsive to the inhibitionof COX-2 and are typically substantially free of undesirablegastrointestinal side effects associated with conventional non-steroidalanti-inflammatory agents.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., rats, mice, dogs, monkeys andisolated cells or enzyme preparations of human and non-human origin.Said compounds can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo advantageously orally, topically orparenterally, e.g., intravenously. The dosage in vitro may range fromabout 10⁻⁵-10⁻⁹ molar concentrations. The dosage in vivo may range,depending on the route of administration, between about 0.1 mg/kg and100 mg/kg.

The biological properties can be demonstrated in tests well-known in theart, e.g., as described in U.S. Pat. No. 6,291,523, and as describedherein.

COX-2 inhibition is determined in an enzymatic in vitro assay using acommercially available kit (Cayman Chemical Company).

The test compound (stock solution in DMSO diluted with buffer to variousconcentrations) is pre-incubated with 30-50 units of purifiedrecombinant human COX-2 and hemactin (1 μM) for 30 minutes at 25° C.,followed by incubation with 100 μM arachidonic acid and the colorimetricsubstrate TMPD (N,N,N′,N′-tetramethyl-p-phenylenediamine) for 5-7minutes at 25° C., followed by colorimetric detection of oxidized TMPDat 590 nm. The COX-2 activity in the presence of test compound iscompared to COX-2 activity for control without test compound.

COX inhibition is also determined in vitro using cellular assays forinhibition of both COX-1 and COX-2.

Cellular assays for testing COX inhibitors are well-known in the art andbased on the fact that the COX enzyme (prostaglandin H synthase)catalyzes the rate limiting step in prostaglandin synthesis fromarachidonic acid. Two enzymes mediate the reaction: COX-1 is aconstitutive form of the enzyme whereas COX-2 is induced in response tovarious growth factors and cytokines.

In vitro COX-1 and COX-2 inhibition is determined in the cell-basedassays in order to assess the in vitro activity and selectivity forCOX-2 inhibition, using a prostaglandin E₂ immunoassay (Cayman PGE₂Kit). The cells utilized are HEK-293 EBNA cells that have beentransfected and have a stable expression of either recombinant humanCOX-1 or recombinant human COX-2, respectively. Cells are plated outinto 96-well plates in which the assay is performed. Both cell lines arepre-treated with compound dilutions for 30 minutes at 37° C., thenarachidonic acid (1 μM) is added as exogenous substrate. The supernatantis harvested 15 minutes later and the production of PGE₂ is measured byimmunoassay. For IC₅₀ determinations, compounds are tested at 5-9concentrations in singlet, duplicate or quadruplicate replicates at eachconcentration (highest concentration 30 μM). The mean inhibition of PGE₂(compared to cells not treated with compound) for each concentration iscalculated, a plot is made of mean % inhibition versus log compoundconcentration, and the IC₅₀ value calculated using a 4-parameterlogistic fit. The relative effects on each enzyme are compared to assessselectivity for inhibition of COX-2.

In vitro COX-1 and COX-2 inhibition is also determined in human wholeblood where COX-1 is constitutively expressed in platelets and COX-2expression is induced in mononuclear cells by treatment withlipopolysaccharide (LPS) (10 μg/mL). For this assay heparinized humanblood is divided into two aliquots: one for measuring TxB₂ production (asurrogate indicator of COX-1 activity) and a second for measuring PGE₂production (a surrogate for COX-2 activity). The blood samples arepretreated with test compounds for one hour before stimulation.Compounds are tested in a final concentration range from 0.1 nM to 300μM using half log increases in concentrations. To measure inhibition ofthromboxane 82 (TxB₂) generation, A23187 (50 μM) is added, and the bloodincubated for one hour. PGE₂ production is measured after the additionof LPS (10 μg/mL) followed by overnight incubation. After incubationwith A23187 or LPS the samples are centrifuged at 250×g for 10 minutesat 4° C. to collect serum. The amounts PGE₂ and TxB₂ present in theserum are measured using a chemiluminescence enzyme immunoassay fromAssay Designs Inc. (Ann Arbor, Mich.). The levels of prostaglandin ineach sample are normalized to the percent inhibition caused by eachconcentration of the test compound. The percent inhibition data for eachdonor is pooled and fitted to a 4-parameter logistic function using aregression.

IC₅₀ values for compounds of formula (I) in the COX-2 inhibition assaysare as low as about 0.10 μM or even lower. Preferred are compounds forwhich the ratio of IC₅₀ values for COX-1 and COX-2 inhibition is above50, advantageously in the range of about 100-1000 or higher. Forexample, the following IC₅₀ values were observed based on the abovedescribed assay, average values being taken where more than one assaywas performed:

COX-2_Blood IC50 COX-1_Blood Example [μM] (Avg) IC50 [μM] (Avg) 5a 0.1155 5e 0.073 126 5i 0.295 129 5k 0.165 183 5m 0.17 127

The inhibition of prostaglandin-E₂ production produced by COX-2 isdetermined in vivo in the lipopolysaccharide (LPS)-challengedsubcutaneous air pouch model in the rat. See Advances in InflammationResearch, Raven Press (1986); J. Med. Chem., Vol. 39, p. 1846 (1996); J.Pathol., Vol. 141, pp. 483-495; and J. Pathol., Vol. 134, pp. 147-156.

Female Lewis rats are anesthetized and then dorsal air pouches areprepared by subcutaneous injection of 10 mL of air through a sterile0.45 micron syringe-adapted filter. Six or 7 days after preparation, theair pouches are injected with LPS (5 μg per pouch) suspended in sterilephosphate buffered saline. Compounds for evaluation are administered bygavage one hour prior to or two or more hours after LPS challenge. Thepouch contents are harvested five hours after LPS challenge and PGE₂levels present in the pouch fluids are measured by enzyme immunoassay.Illustrative of the invention, the compound of Example 4(j) inhibitsPGE₂ formation by about 50% at 1 mg/kg p.o.

Anti-inflammatory activity is determined using the carrageenan-inducedrat paw edema assay following a modification of the procedure ofOfferness et al., described in: Nonsteroidal Antiinflammatory Drugs,Lombardino, Ed., John Wiley & Sons, pp. 116-128 (1986).

Sprague Dawley rats (200-225 g) are fasted overnight, then orally dosedwith the compound dissolved in 0.5% methylcellulose. After one hour, a0.1 mL volume of 1% carrageenan in saline is injected into thesub-plantar region of the left hind paw which causes an inflammatoryresponse. At three hours post-carrageenan, the rats are euthanized andboth hind paws are cut off at the paw hair line and weighed on anelectronic balance. The amount of edema in the inflamed paw isdetermined by subtracting the weight of the non-inflamed paw (right)from the weight of the inflamed paw (left). The percent inhibition bythe compound is determined for each animal as the percent paw weightgained as compared to the control average.

The gastric tolerability assay is used to assess gross ulceration in therat, measured four hours after oral administration of the test compound.The test is carried out as follows:

Male Sprague Dawley rats are fasted overnight, administered compound in0.5% methylcellulose vehicle by gavage and sacrificed by carbon dioxideinhalation four hours later. The stomachs are removed and gross gastriclesions counted and measured to give the total lesion length per rat.Each experiment contains the following groups (5-6 rats per group):vehicle control, test compounds and diclofenac as a reference compound.

Data are calculated as the mean number of ulcers in a group, the meanlength of ulcers (mm) in the group and as the ulcer index (UI).

UI=mean length of ulcers in a group×ulcer incidence

where ulcer incidence is the fraction of animals in the group withlesions (100% incidence is 1).

Illustrative of the invention, the compounds of the Examples areessentially free of any gastric ulcerogenic effect at 30 mg/kg p.o.

Intestinal tolerability can be determined by measuring the effect onintestinal permeability. Lack of increase in permeability is indicativeof intestinal tolerability.

The method used is a modification of a procedure by Davies et al.,Pharm. Res., Vol. 11, pp. 1652-1656 (1994) and is based on the fact thatexcretion of orally administered ⁵¹Cr-EDTA, a marker of small intestinalpermeability, is increased by NSAIDs. Groups of male Sprague Dawley rats(≧12 per group) are administered a single, oral dose of test compound orvehicle by gastric intubation. Immediately following compound dose, eachrat is administered ⁵¹Cr-EDTA (5 μCi per rat) by gastric intubation. Therats are placed in individual metabolic cages and given food and waterad libitum. Urine is collected over a 24-hour period. Twenty-four hoursafter administration of ⁵¹Cr-EDTA the rats are sacrificed. To quantifycompound effect on intestinal permeability, the excreted ⁵¹Cr-EDTAmeasured in the urine of compound-treated rats is compared to theexcreted ⁵¹Cr-EDTA measured in the urine of vehicle-treated rats.Relative permeability is determined by calculating the activity presentin each urine sample as a percent of the administered dose aftercorrecting for background radiation.

The analgesic activity of the compounds of the invention is determinedusing the complete Freund's adjuvant (CFA)-induced hyperalgesia asmeasured in the rat. Fifty μl of CFA is injected into the left hind paw.Nociceptive thresholds are determined prior to 24 hrs following CFAinjection using standard paw-pressure apparatus (Analgesymeter, UgoBasile, Milan). The end point is taken as paw withdrawal or struggling.Compounds are dissolved in 0.5% methylcellulose and administered orally,and further nociceptive threshold measurements are made at 1, 3 and 6 hfollowing drug administration. In each experiment groups of 6 animalsreceived either vehicle or one dose of compound. The results arecalculated as percentage reversal of predose hyperalgesia. The dose atwhich 30% inhibition of the predose hyperalgesia is achieved (D30) foreach compound is calculated to give an overall estimate of potency.

The anti-arthritic effect of the compounds of the invention can bedetermined in the well-known chronic adjuvant arthritis test in the rat.

Ocular effects can be demonstrated in well-known ophthalmic assaymethods. Similarly anti-tumor activity can be demonstrated in well-knownanti-tumor animal tests.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal, topical andparenteral administration to mammals, including man, to inhibitCOX-2-activity, and for the treatment of COX-2 dependent disorders, andcomprise an effective amount of a pharmacologically active compound ofthe invention, either alone or in combination with other therapeuticagents, and one or more pharmaceutically acceptable carriers.

More particularly, the pharmaceutical compositions comprise an effectiveCOX-2 inhibiting amount of a selective COX-2 inhibiting compound of theinvention which is substantially free of COX-1 inhibiting activity andof side effects attributed thereto.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable formulations for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. In thisregard it is noted that compounds of the present invention are capableof absorbing UV rays in the range of 290-320 nm while allowing passageof tanning rays at higher wavelengths. They are thus particularly suitedfor use in topical, including cosmetic, formulations well-known in theart. Such may contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives. Formulations suitable for topicalapplication can be prepared, e.g., as described in U.S. Pat. No.4,784,808. Formulations for ocular administration can be prepared, e.g.,as described in U.S. Pat. Nos. 4,829,088 and 4,960,799.

The compounds of the invention may be used alone or in conjunction withother therapeutic agents. For example, suitable additional active agentsfor use in relation to the treatment of neoplasia (malignant and benign)include, e.g., the anti-neoplastic agents or radioprotective agentsrecited in International Patent Application WO 98/16227 and the like.Other suitable additional therapeutic agents include analgesic agents,such as NSAIDs, oxycodone, codeine, paracetamol, ibuprofen, tramadol,levorphanol, propoxyphene, ketorolac, pentazocine, meperidine and thelike; muscle relaxants, e.g. benzothiadiazoles e.g. Sirdalud®; alsoanti-platelet agents, such as aspirin, clopidogrel, ticlopidine and thelike; also bisphosphonates, such as zoledronate, pamidronate,risedronate, alendronate and the like; also statins, such asfluvastatin, atorvastatin, lovastatin, simvastatin, rosuvastatin,pitavastatin, pravastatin and the like; also antacids; proton pumpinhibitors e.g. omeprazole, esomeprazole; calcilytics; calcitonin, e.g.oral calcitonin; an anti-IL-1beta IgG1/kappa antibody;antihypertensives, e.g. ACE inhibitors, angiotensin 11 blockers, renininhibitors.

In conjunction with another active ingredient, a compound of theinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 50-70 kg may contain between about 5mg and 500 mg, of the active ingredient.

The present invention also relates to methods of using the compounds ofthe invention and their pharmaceutically acceptable salts, orpharmaceutical compositions thereof, in mammals for inhibiting COX-2 andfor the treatment of conditions as described herein, e.g., inflammation,pain, rheumatoid arthritis, osteoarthritis, dysmenorrheal, tumors andother COX-2-dependent disorders.

Particularly, the present invention relates to a method of selectivelyinhibiting COX-2 activity in a mammal without substantially inhibitingCOX-1 activity, which comprises administering to a mammal in needthereof an effective COX-2 inhibiting amount of a compound of theinvention.

Thus, the present invention also relates to a method of treating COX-2dependent disorders in mammals, which comprises administering to amammal in need thereof an effective COX-2 inhibiting amount of acompound of the invention.

More particularly, the present invention relates to a method of treatingCOX-2 dependent disorders in mammals while substantially eliminatingundesirable side effects associated with COX-1 inhibiting activity whichcomprises administering to a mammal in need thereof an effective COX-2inhibiting amount of a selective COX-2 inhibiting compound of theinvention which is substantially free of COX-1 inhibiting activity.

More specifically, such relates to a method of, e.g., treatingrheumatoid arthritis, osteoarthritis, pain, dysmenorrheal, gout orinflammation in mammals without causing undesirable gastrointestinalulceration, which method comprises administering to a mammal in needthereof a correspondingly effective amount of a compound of theinvention.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR andNMR. Abbreviations and tradenames used are those conventional in theart. Typical are those given below

BOC: t-butoxycarbonylCOD: cyclooctadieneDMAP: 4-dimethylamino-pyridine

DME: 1,2-Dimethoxyethane

DSC: differential scanning calorimetry

DMF: N,N-dimethylformamide

dppp: diphenylphospinopropaneEDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideHOAt: 1-hydroxy-7-azabenzotriazoleLAH: lithium aluminum hydride

NMM: N-methylmorpholine

Selectfluor™: 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)THF: tetrahydrofuranTLC: thin layer chromatography

EXAMPLES Example 1 Starting Materials A. 2,4-Dichloro-3-methylaniline

2,4-Dichloro-3-methylaniline is prepared by reduction of2,4-dichloro-3-methylnitrobenzene according to the procedure outlined inTetrahedron, Vol. 53, No. 17, p. 6145 (1997).

B. 2,4-Dichloro-3-ethylaniline

To a solution of 2,4-dichloroaniline (42.0 g, 260 mmol) in AcOH (40.0mL) is added Ac₂O (80 mL). The reaction mixture is warmed up to 50° C.and stirred at this temperature for 1 hour. The reaction is cooled toroom temperature and poured into ice water (500 mL). A solidprecipitated and the mixture is stirred for additional 1 hour at roomtemperature. The solid is filtered and washed with water, hexanes andair dried to give N-(2,4-dichlorophenyl)acetamide.

To a solution of N-(4-chloro-2-fluorophenyl)acetamide (30.0 g, 147 mmol)in THF (300 mL) at −70° C. is added dropwise (keeping the reactiontemperature below −60° C.) n-BuLi (2.0 M in cyclohexane, 147 mL, 294mmol). The reaction is stirred between −60 to −70° C. for 2 hours and1,1,1-trifluoro-2-iodoethane (46.2 g, 220 mmol) is added dropwise at−70° C. The reaction mixture is stirred at this temperature foradditional 1.5 hours before 3N HCl (108 mL) solution is added slowly.The mixture is allowed to warm up to room temperature and extracted withEtOAc (200 mL×3). The organic layers are combined washed with water,brine and then dried over MgSO₄. The solvents are removed and theresidue is stirred in ether and hexanes (1:2, 120 mL) for 1 hour. Asolid precipitate is filtered to giveN-(2,4-dichloro-3-iodophenyl)acetamide.

To a solution of N-(2,4-dichloro-3-iodophenyl)acetamide (40.0 g, 121mmol) in MeOH (100 mL) is added concentrated HCl (50 mL). The mixture isstirred and heated at reflux for 18 hours. The mixture is cooled and thesolvents were removed under reduced pressure (water bath below 45° C.).The residue is cooled with an ice bath and 3N NaOH solution was added toadjust the pH to between 9 and 10. The mixture is extracted with etherand dried over MgSO₄. The solvents were removed and the residue ispurified through a flash chromatographic column with a gradient ofhexanes/ether to give 2,4-dichloro-3-iodoaniline.

To a solution of 2,4-dichloro-3-iodoaniline (9.0 g, 31 mmol) inDME/water (180 mLU60 mL) is added vinyl triboroxine pyridine complex(5.0 g, 20.8 mmol) and K₂CO₃ (8.5 g, 62.0 mmol). The reaction mixture isstirred and N₂ is bubbled in for 15 min. Tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.6 mmol) is added at room temperature and N₂ isbubbled in for additional 20 min. The reaction mixture is heated to 80°C. and stirred for 18 hours, when the GC-MS showed the reaction iscomplete. The mixture is filtered and washed with ether (400 mL) andwater (50 mL). The organic layer is separated and washed with brine anddried over MgSO₄. The solvents were removed and the residue is purifiedthrough a flash chromatographic column with a gradient of hexanes/etherto give 2,4-dichloro-3-vinylaniline.

To a solution of 2,4-dichloro-3-vinylaniline (4.9 g, 26 mmol) in EtOAc(60 mL) is added 10% Pd/C (0.50 g). The pressure flask is filled with H₂at 55 psi and shaken for 2 hrs. Excess H₂ is removed and the mixture isfiltered through a pad of celite. The solvent is removed and theresulting mixture is purified through a flash chromatographic columnwith a gradient of hexanes/ether to give 2,4-dichloro-3-ethylaniline.

C. 2-Fluoro-4-methyl-3-trifluoroaniline

To a solution of 2-fluoro-3-trifluoromethylaniline (5.0 g, 28 mmol) inDMF (25 mL) is added a solution of NBS (5.0 g, 28 mmol) in DMF (25 mL).After 2.5 h, the reaction is partitioned between ether and saturatedaqueous NaCl. The separated organic phase is washed twice with freshsaturated aqueous NaCl, dried over Na₂SO₄, and concentrated underreduced pressure to give 4-bromo-2-fluoro-3-trifluoromethylaniline as anoil.

The bromide above (10.0 g, 38.8 mmol), trimethylboroxine (4.9 g, 38.8mmol), K₂CO₃ (16.1 g, 116 mmol), and palladiumtetrakistriphenylphosphine (4.5 g, 3.9 mmol) are heated under a nitrogenatmosphere. A second aliquot of trimethylboroxine (4.9 g, 38.8 mmol) isadded to consume the starting bromide. After 18 h, the cooled reactionis partitioned between EtOAc and saturated aqueous NaCl. The separatedorganic layer is washed with fresh brine (3×), dried with Na₂SO₄, andconcentrated under reduced pressure. The residue is purified by flashchromatography (Et₂O/hexanes) to give the title aniline.

D. 2-Fluoro-4-ethyl-3-trifluoroaniline

4-Bromo-2-fluoro-3-trifluoromethylaniline described above (5.0 g, 19.4mmol) and tributylvinyltin chloride (7.1 g, 20.4 mmol) are added toanhydrous DMF (100 mL). The solution is degassed with N₂, palladiumtetrakistriphenylphosphine (1.5 g, 1.3 mmol) is added, and the reactionis heated at 120° C. for 18 hours. After cooling, the reaction mixtureis partitioned between Et₂O and saturated aqueous NaCl. The separatedether layer is washed with fresh saturated aqueous NaCl (2×), dried withNa₂SO₄, and concentrated under reduced pressure. The residue is purifiedby flash chromatography eluting with 5, then 10, then 20% EtOAc inhexanes to give the desired product,2-fluoro-3-trifluoromethyl-4-vinylaniline.

2-Fluoro-3-trifluoromethyl-4-vinylaniline prepared above (4.0 g, 19.4mmol) is dissolved in EtOH and degassed with N₂, and 10% Pd on charcoal(0.5 g) is added. The mixture is placed in a Parr apparatus and treatedwith H₂ at room temperature. The reaction is flushed with N₂ andfiltered. The filter pad is washed with fresh EtOH and the filtrates arecombined. Concentrated HCl (6.5 mL) is added to the cooled filtrate (0°C.) before removal of the volatiles under reduced pressure. Theresulting white solid is washed with Et₂O and collected by filtration togive 4-ethyl-2-fluoro-3-trifluoromethylaniline hydrochloride.

The free aniline is prepared from the hydrochloride salt by partitioningbetween Et₂O and a saturated aqueous NaHCO₃ solution. The separatedorganic layer is washed with brine, dried (Na₂SO₄) and concentrated invacuo to give 4-ethyl-2-fluoro-3-trifluoromethylaniline as an oil.

E. 4-Chloro-2-fluoro-3-methylaniline

To 6-chloro-2-fluoro-3-methylbenzoic acid (10 g, 53 mmol) is addedCH₂Cl₂ (60 mL), DMF (0.5 mL) and oxalyl chloride (9.25 mL, 106 mmol).The reaction mixture is allowed to stir until it reaches homogeneity andis then concentrated in vacuo. The residue is poured onto a 50:50mixture of ice and 36% ammonium hydroxide to yield6-chloro-2-fluoro-3-methylbenzamide.

The 6-chloro-2-fluoro-3-methylbenzamide prepared above is dissolved inMeOH. Sodium methoxide (16.1 g, 298 mmol) is added and the reaction isheated to reflux. NBS (21.2 g, 119 mmol) is then added portionwise as asolid and the reaction mixture is stirred at reflux an additional 2hours. After cooling, volatiles are removed under reduced pressure andthe residue is diluted with EtOAc and water. The organic phase isseparated and the water layer is extracted with fresh EtOAc (3×). Thecombined organic layers are dried (MgSO₄), filtered and concentrated invacuo to give N-6-chloro-2-fluoro-3-methyl-phenyl)carbamic acid methylester.

The carbamate prepared above is dissolved in MeOH (220 mL) and water (22mL). Potassium hydroxide (31 g, 560 mmol) is added and the reactionheated at reflux for 12 hours. After cooling the reaction to roomtemperature, the MeOH is removed under reduced pressure and the residueis diluted with water and extracted with CH₂Cl₂ (3×). The combinedorganic layers are dried (MgSO₄), filtered and concentrated in vacuo.The residue is purified by flash chromatography using 10% EtOAc inhexane to give 6-chloro-2-fluoro-3-methylaniline.

To 6-chloro-2-fluoro-3-methylbenzoic acid (10 g, 53 mmol) is addedCH₂Cl₂ (60 mL), DMF (0.5 mL) and oxalyl chloride (9.25 mL, 106 mmol).The reaction mixture is allowed to stir until it reaches homogeneity andis then concentrated in vacuo. The residue is poured onto a 50:50mixture of ice: 36% ammonium hydroxide to yield6-chloro-2-fluoro-3-methylbenzamide.

The 6-chloro-2-fluoro-3-methylbenzamide prepared above is dissolved inMeOH. Sodium methoxide (16.1 g, 298 mmol) is added and the reaction isheated to reflux. NBS (21.2 g, 119 mmol) is then added portionwise as asolid and the reaction mixture is stirred at reflux an additional 2hours. After cooling, volatiles are removed under reduced pressure andthe residue is diluted with EtOAc and water. The organic phase isseparated and the water layer is extracted with fresh EtOAc (3×). Thecombined organic layers are dried (MgSO₄), filtered and concentrated invacuo to give N-6-chloro-2-fluoro-3-methyl-phenyl)carbamic acid methylester.

The carbamate prepared above is dissolved in MeOH (220 mL) and water (22mL). Potassium hydroxide (31 g, 560 mmol) is added and the reactionheated at reflux for 12 hours. After cooling the reaction to roomtemperature, the MeOH is removed under reduced pressure and the residueis diluted with water and extracted with CH₂Cl₂ (3×). The combinedorganic layers are dried (MgSO₄), filtered and concentrated in vacuo.The residue is purified by flash chromatography using 10% EtOAc inhexane to give 6-chloro-2-fluoro-3-methylaniline.

F. 4-Chloro-2-fluoro-3-ethylaniline

To a solution of 4-chloro-2-fluoroaniline (50.0 g, 344 mmol) in AcOH (30mL) is added Ac₂O (60 mL) and the reaction is stirred at roomtemperature for 2 hours. The mixture is poured into ice water (500 mL)to give a solid precipitate. The mixture is stirred for an additional 1hour at room temperature. The solid is filtered and washed with waterand hexanes, then air dried to giveN-(4-chloro-2-fluorophenyl)acetamide.

To a solution of N-(4-chloro-2-fluorophenyl)acetamide (10.0 g, 53.3mmol) and diisopropylamine (7.5 mL, 53.3 mmol) in THF (300 mL) at −78°C. is added dropwise n-BuLi (2.5 M in hexanes, 42.6 mL, 106.6 mmol)keeping the reaction temperature below −60° C. After 2 hours, iodoethane(12.4 g, 80 mmol) is added dropwise at −78° C. The reaction mixture isstirred at −78° C. for additional 1.5 hours. A 1N solution of aqueousHCl is added slowly until a pH between 4 and 5 is reached. The mixtureis extracted with EtOAc (200 mL×3) and the organic layers are combinedwashed with water and brine, then dried over MgSO₄. The solvent isremoved under reduced pressure and the solid residue is stirred in etherand hexane (1:4, 80 mL) for 1 hour. The filtered solid is dried to giveN-4-chloro-3-ethyl-2-fluorophenyl)acetamide.

To a solution of N-(4-chloro-3-ethyl-2-fluorophenyl)acetamide (11.0 g,51.0 mmol) in MeOH (80 mL) is added concentrated HCl (40 mL) beforeheating at reflux for 16 hours. The solvent is removed from the cooledreaction under reduced pressure maintaining the water bath below 45° C.The residue is cooled with an ice bath before a 3N NaOH solution isadded to adjust pH between 9 and 10. The mixture is extracted with etherand dried over MgSO₄. The solvent is removed and the residue is purifiedthrough a flash chromatography using a gradient of ether/hexanes to give4-chloro-3-ethyl-2-fluoroaniline.

Similarly prepared is:

-   4-chloro-3-methyl-2-fluoroaniline.

G. 4-Chloro-2-fluoro-3-isopropylaniline

To a solution of N-(4-chloro-2-fluorophenyl)acetamide prepared above(12.0 g, 64 mmol) in THF (300 mL) at −78° C. is added dropwise n-BuLi(2.0 M in cyclohexane, 64 mL, 128 mmol) keeping the reaction temperaturebelow −60° C. The reaction mixture is stirred between −60 to −70° C. for2 hours and 1,1,1-trifluoro-2-iodoethane (20.1 g, 96 mmol) is addeddropwise at −78° C. The mixture is stirred at this temperature foradditional 3 hrs. Then a 1N HCl (200 mL) solution is added slowly at−78° C. The mixture is allowed to warm to room temperature and extractedwith EtOAc (200 mL×3). The combined organic layers are washed with waterand brine, then dried over MgSO₄. The solvent is removed and the residueis stirred in ether and hexanes (1:2, 120 mL) for 1 hour. The solid isfiltered to give N-(4-chloro-2-fluoro-3-iodophenyl)acetamide.

To a mixture of N-(4-chloro-2-fluoro-3-iodophenyl)acetamide (20.0 g, 64mmol) in MeOH (80 mL) is added concentrated HCl (60 mL). The mixture isstirred at reflux for 18 hours before cooling to room temperature andremoval of the solvent under reduced pressure while maintaining thewater bath below 45° C. The residue is cooled with an ice bath and a 1NNaOH solution is added to adjust the pH between 9 and 10. The aqueousphase is extracted with ether and dried over MgSO₄. The solvent isremoved and the residue is purified through a flash chromatographiccolumn with a gradient of hexanes/ether to give4-chloro-2-fluoro-3-iodoaniline.

To a solution of 4-chloro-2-fluoro-3-iodoaniline (13.5 g, 50 mmol) inDME/water (150 mL/50 mL) is added 2-propeneboronic acid (6.4 g, 74.6mmol) and K₂CO₃ (20.6 g, 150 mmol). Nitrogen gas is bubbled in for 15min before tetrakis(triphenylphosphine) palladium(0) (2.8 g, 2.5 mmol)is added at room temperature. Nitrogen is bubbled in for additional 20minutes before the reaction mixture is heated to 80° C. for 18 hours.The mixture is filtered through a pad of celite and washed with ether(400 mL) and water (50 mL). The organic layer is separated and washedwith brine and dried over MgSO₄. The solvent is removed and the residueis purified through a flash chromatographic column with a gradient ofhexanes/ether to give 4-chloro-3-isopropene-2-fluoroaniline.

To a solution of 4-chloro-3-isopropene-2-fluoroaniline (4.5 g, 24.2mmol) in EtOAc (50 mL) is added 10% Pt/C (0.45 g). The pressure flask isfilled with H₂ at 50 psi and shaken at room temperature for 4 hrs. Theexcess H₂ is removed and the mixture is filtered through a pad ofcelite. The solvent is removed and the resulting mixture is purifiedthrough a flash chromatographic column with a gradient of hexanes/etherto give 4-chloro-3-isopropane-2-fluoroaniline.

Example 2 2-Iodophenylacetic Acid Ester and Phenylacetamide StartingMaterials

Prepared according to, e.g., J Med Chem, Vol. 33, pp. 2358-2368 (1990),U.S. Pat. No. 6,291,523 and International Application WO 99/11605,starting from the corresponding benzoic acid or 2-indolinone, are, forinstance:

-   N,N-dimethyl-5-methyl-2-iodophenylacetamide;-   N,N-dimethyl-5-ethyl-2-iodophenylacetamide;

Example 35-Ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide

A mixture of N,N-dimethyl-5-ethyl-2-iodophenylacetamide (2.0 g, 6.3mmol), 2-fluoro-methyl-3-trifluoromethylaniline (2.4 g, 12.6 mmol),copper (0.2 g, 3.2 mmol), cuprous iodide (0.6 g, 3.2 mmol), and K₂CO₃(0.9 g, 6.3 mmol) in xylenes (6.0 mL) are heated at reflux for 24 h.After cooling, the crude reaction mixture is diluted with EtOAc andfiltered through Celite®. The filtrate is concentrated under reducedpressure. The residue is purified by flash chromatography, eluting withhexanes, then up to 25% EtOAc/hexane mixtures to give the targetcompound5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide.

Similarly prepared are:

-   5-Methyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic    acid N,N-dimethyl amide.-   5-Methyl-2-(2′-fluoro-4′-bromo-3′-trifluoromethylanilino)phenylacetic    acid N,N-dimethyl amide.-   5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Ethyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Methyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Ethyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Methyl-2-(2′-fluoro-4′-chloro-3′-methylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Ethyl-2-(2′-fluoro-4′-chloro-3′-methylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Methyl-2-(2′-fluoro-4′-chloro-3′-ethylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Ethyl-2-(2′-fluoro-4′-chloro-3′-ethylanilino)phenylacetic acid    N,N-dimethyl amide.-   5-Ethyl-2-(2′-fluoro-4′-chloro-3′-isopropylanilino)phenylacetic acid    N,N-dimethyl amide.

Example 45-Methyl-2-(2′-fluoro-4′-ethyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide

5-Methyl-2-(2′-fluoro-4′-bromo-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide prepared by method outlined in example 3 (0.8 g,1.7 mmol), Pd(PPh₃)₄ (0.1 g, 0.09 mmol), and vinyl tributylstannane (0.6g, 1.9 mmol) in DMF (5 mL) is heated to 120° C. under nitrogenovernight. After cooling, the reaction is portioned between EtOAc andsaturated aqueous solution of NaCl. The separated organic layer iswashed twice with fresh saturated aqueous solution of NaCl. The EtOAclayer is dried and concentrated under reduced pressure. The residue ispurified by flash chromatography to give5-Methyl-2-(2′-fluor-4′-vinyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide.

The above styrene is reduced under conditions outlined in. The styreneis dissolved in i-PrOH and toluene and degassed for 10 minutes. ThenCs₂CO₃ (22 mg, 0.07 mmol), [Ir(cod)Cl]₂ (44 mg, 0.07 mmol), and dppp (27mg, 0.07 mmol) are added and the reaction is heated to 80° C. overnight. The cooled solution is concentrated in vacuo and the residuepurified by flash chromatography eluting with 10, then 20, then 30%EtOAc/hexanes to give the title5-methyl-2-(2′-fluoro-4′-ethyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide.

Example 5 5a)5-Ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid

A solution of the above5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid N,N-dimethyl amide described in Example 3 (0.9 g, 2,4 mmol) in EtOH(25 mL) and 4N NaOH (12 mL) is heated to 80° C. overnight. Aftercooling, the reaction is concentrated under reduced pressure and dilutedwith ice cold EtOAc. The pH of the aqueous layer is adjusted to 1-2 withice cold 2.5 N HCl. The separated organic layer is dried with Na₂SO₄ andconcentrated to a solid. The solid is purified by trituration with anEt₂O/hexane mixture to give the title acid,5-ethyl-2-2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid.

MS m/z 356 (ES⁺), 354 (ES⁻)

CHN found C 60.47, H 4.47, N 3.73.

Similarly prepared are:

5b)5-Methyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylaceticacid

MS m/z 342 (ES⁺), 340 (ES⁻)

CHN found C 59.56, H 4.36, N 3.91.

5c)5-Methyl-2-(2′-fluoro-4′-ethyl-3′-trifluoromethylanilino)phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (t, J=7.3 Hz, 3H), 2.27 (s, 3H),2.63-2.70 (m, 2H), 3.56 (s, 2H), 6.87 (t, J=8.6 Hz, 1H), 7.02-7.09 (m,2H), 7.12 (s, 1H), 7.43 (s, 1H).

MS m/z 356 (ES⁺), 354 (ES⁻)

5d) 5-Ethyl-2-(2′-fluoro-4′-ethyl-3′-trifluoromethylanilino)phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, J=7.5 Hz, 3H), 1.26 (t, J=7.5Hz, 3H), 2.59 (q, J=7.5 Hz, 2H), 2.89 (q, J=7.1 Hz, 2H), 3.75 (d, J=22.7Hz 1H), 3.83 (d, J=22.7 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.1Hz, 1H), 7.23 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H).

MS m/z 370 (ES⁺), 368 (ES⁻)

5e) 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid

¹H NMR (400 MHz, DMSO-de) δ ppm 2.29 (s, 3H), 2.41 (s, 3H), 3.51 (s,2H), 6.51 (d, J=8.8 Hz, 1H), 7.07-7.22 (m, 4H), 12.46 (s, 1H)

MS m/z 324, 326, 328 (ES⁺), 322, 324, 326 (ES⁻)

5f) 5-Ethyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid

MS m/z 338, 340, 342 (ES⁺), 336, 338, 340 (ES⁻)

CHN found C 59.97, H 4.71, N 4.12.

5g) 5-Methyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.5 Hz, 3H), 2.29 (s, 3H),2.88 (q, J=7.5 Hz, 2H), 3.52 (s, 2H), 6.52 (d, J=9.0 Hz, 1H), 7.07-7.18(m, 4H), 7.25 (s, 1H), 12.49 (br. s., 1H)

CHN found C 60.53, H 5.19, N 3.98.

5h) 5-Ethyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.22 (m, 6H), 2.52-2.63 (m, 4H),2.88 (q, J=7.5 Hz, 2H), 3.54 (s, 2H), 6.55 (d, J=9.0 Hz, 1H), 7.11-7.15(m, 3H), 7.18 (s, 1H), 7.26 (s, 1H), 12.50 (br. s., 1H)

CHN found C 61.39, H 5.22, N 4.24.

5i) 5-Methyl-2-(2′-fluoro-4′-chloro-3′-methylanilino)phenylacetic acid

MS m/z 308 (ES⁺), 306 (ES⁻)

CHN found C 62.16, H 4.79, N 4.49.

5j) 5-Ethyl-2-(2′-fluoro-4′-chloro-3′-methylanilino)phenylacetic acid

MS m/z 322 (ES⁺), 320 (ES⁻)

CHN found C 63.20, H 5.22, N 4.32.

5k) 5-Methyl-2-2′-fluoro-4′-chloro-3′-ethylanilino)phenylacetic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.5 Hz, 3H), 2.27 (s, 3H),2.72 (qd, J=7.5, 2.1 Hz, 2H), 3.54 (s, 2H), 6.55 (t, J=9.0 Hz, 1H),6.98-7.07 (m, 3H), 7.10 (s, 1H), 7.30 (br. s., 1H), 12.35 (br. s., 1H)

MS m/z 322 (ES⁺), 320 (ES⁻)

CHN found C 63.54, H 5.28, N 4.38.

5l) 5-Ethyl-2-(2′-fluoro-4′-chloro-3′-ethylanilino)phenylacetic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.20 (m, 6H), 2.57 (q, J=7.7 Hz,2H), 2.68-2.76 (m, 2H), 3.56 (s, 2H), 6.58 (t, J=9.0 Hz, 1H), 7.00 (dd,J=9.0, 1.5 Hz, 1H), 7.04-7.10 (m, 2H), 7.13 (s, 1H), 7.31 (s, 1H), 12.36(s, 1H)

CHN found C 64.20, H 5.61, N 4.37.

5m) 5-Ethyl-2-(2′-fluoro-4′-chloro-3′-isopropylanilino)phenylacetic acid

¹H NMR (400 MHz, CDCl₃) δ ppm 1.23 (t, J=7.7 Hz, 3H), 1.37 (dd, J=7.0,1.3 Hz, 6H), 2.62 (q, J=7.7 Hz, 2H), 3.46-3.60 (m, 1H), 3.68 (s, 2H),6.72 (t, J=8.8 Hz, 1H), 6.92 (dd, J=8.8, 1.8 Hz, 1H), 7.07-7.14 (m, 2H),7.23 (d, J=8.1 Hz, 1H)

CHN found C, 65.08; H, 6.16; N, 3.84.

Example 6 6a) 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylaceticacid diethylamine salt

A suspension of 600 mg5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (1.85mmoles) in 6 ml tert. Butyl methyl ether (TBME) is heated to 40° C. 137mg diethylamine (1.85 mmoles) are dropwise added. The resulting slightlycloudy solution is clarified via hot filtration through a Whatmanglasfiber filter. The filter is rinsed with 2 ml TBME of 40° C. Thefiltrate is allowed to cool slowly.

The solution is seeded at 30° C. and crystallization takes place. Thesuspension is stirred for ca. 15 h at room temperature and then for 2 hat 0° C. The slurry is filtered and the filter cake washed with 4.5 mlTBME of 0° C. The crystals are dried for 4 h at 50° C. and ca. 10 mbarto yield a white powder, m.p. 115-116° C.

6b) sodium 5-Methyl-242′,4′-dichloro-3′-methylanilino)phenylacetate

A suspension of 400 mg5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (1.23mmoles) in 4 ml acetone is heated to 50° C. The resulting almost clearsolution is clarified via hot filtration through a Whatman glasfiberfilter. The filter is rinsed with 2 ml acetone of 50° C. 165 mg 30%aqueous natriumhydroxide solution (1.23 mmoles) are added at 50° C. Thesolution is allowed to cool to room temp. and seeded at ca. 25° C.Crystallization takes then very slowly place. The suspension is stirredfor ca. 15 h at room temperature and then for 2 h at 0° C. Afterfiltration only 97 mg wet crystals are obtained. The crystals and themother liquor are combined and 6 ml isopropylacetate are added dropwiseunder stirring. The thick suspension is filtered and the solid washedwith isopropylacetate. The salt is dried first for 2 h at 50° C./ca. 10mbar and then for 16 h at 80° C. and ca. 10 mbar to yield the salt as awhite powder, m.p. 254-255° C.

Water assay: 2.31% m/m

6c) 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acidtromethamine salt

A suspension of 1.30 g5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (4.01mmoles) in 13 ml acetone is heated to 55° C.

The resulting almost clear solution is clarified via hot filtrationthrough a Whatman glasfiber filter. The filter is rinsed with 2.6 mlacetone of 50° C. A solution of 0.487 g tromethamine (Trisma base) (4.01mmoles) in 1 ml water is added dropwise at 50° C. The dropping funnel isrinsed with 0.5 ml water. The solution is allowed to cool to room temp.and seeded at ca. 40° C. Crystallization takes then place. Thesuspension is stirred for ca. 15 h at room temperature and then for 2 hat 0° C. The slurry is filtered and the solid washed with 6 ml acetone.The salt is dried first for 2 h at 50° C./ca. 10 mbar and then for 16 hat 80° C. and ca. 10 mbar to yield the salt as a white powder, m.p.156-157° C., DSC 162.0° C., melting enthalpy 132 J/g.

Prinicipal X-ray diffraction peaks: Angle d value Intensity 2-Theta °Angstrom Count Intensity % 4.371 20.19907 360 66.7 13.276 6.66382 52597.2 13.719 6.44934 312 57.8 14.443 6.12802 316 58.5 14.943 5.9239 35665.9 15.663 5.65321 318 58.9 16.948 5.22734 403 74.6 17.739 4.99598 30456.3 22.832 3.89177 464 85.9 23.707 3.75003 389 72 24.877 3.57629 32359.8 25.868 3.44143 217 40.2 26.596 3.34886 540 100

6d) calcium 5-Methyl-242′,4′-dichloro-3′-methylanilino)phenylacetatemonohydrate

A suspension of 1.30 g5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (4.01mmoles) in 13 ml acetone is heated to 55° C. 0.535 g 30% aqueous sodiumhydroxide solution (4.01 mmoles) are added. The resulting almost clearsolution is clarified via filtration at 50° C. through a Whatmanglasfiber filter. The filter is rinsed with 3.9 ml acetone of 50° C.Then a solution of 0.51 g calciumchloride (4.41 mmoles) in 1 ml water isadded dropwise at 50° C. The dropping funnel is rinsed with 0.5 mlwater. The resulting thick suspension is allowed to cool to roomtemperature. Further 7 ml water are added at 25° C. The mixture isstirred at r.t. for 1 h and filtered. The filter cake is washed with 20ml acetone/water 2:1 v/v and then with 5 ml acetone. the crystallisateis dried for 2 h at 50° C./ca. 10 mbar and then for 16 h at 80° C. andca. 10 mbar. As the salt is still contaminated with some natriumchloridethe crystals are suspended in 13.5 ml water and 1.5 ml acetone and thesuspension stirred for 1 h at r.t. After filtration the filter cake iswashed with 8 ml water/acetone 9:1 v/v in 4 portions. The salt is driedfirst for 2 h at 50° C./ca. 10 mbar and then for 16 h at 80° C. and ca.10 mbarto yield a white powder, m.p. 278-279° C., DSC 147.1/224.2° C.,melting enthalpy 121/2 J/g.

Water assay: 2.63% m/m

Prinicipal X-ray diffraction peaks: Angle d value 2-Theta ° AngstromIntensity % 6.273 14.07919 100 10.622 8.32204 30.7 11.106 7.96028 34.813.38 6.61206 33.7 14.348 6.16798 25.5 16.473 5.37693 48.2 18.6344.75806 29.2 21.394 4.15001 34.7 23.887 3.72226 27.8 24.498 3.63067 23.525.395 3.5045 19

6e) Lysine 5-Methyl-2-2′,4′-dichloro-3′-methylanilino)phenylacetatemonohydrate

A suspension of 400 mg5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (1.23mmoles) in 4 ml acetone is heated to 50° C. The resulting almost clearsolution is clarified via hot filtration through a Whatman glasfiberfilter. The filter is rinsed with 4 ml acetone of 50° C. A solution of184 mg lysine (1.23 mmoles) in 1 ml water is added dropwise. Theresulting thick suspension is kept for 30 min. at 50° C. and thenallowed to cool to room temperature. The mixture is further stirred atca. 25° C. over night and filtered. The filter cake is washed with 6 mlacetone. The crystals are dried first for 2 h at 50° C./ca. 10 mbar andthen for 16 h at 80° C. and ca. 10 mbar to yield a white powder, m.p.162-163° C.

Water assay: 3.80% m/m

6f) choline 5-Methyl-242′,4′-dichloro-3′-methylanilino)phenylacetatemonohydrate

A suspension of 400 mg5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (1.23mmoles) in 4 ml acetone is heated to 50° C. 305 mg chlorine solution 50%in water (1.23 mmoles) are added. The resulting almost clear solution isclarified via hot filtration through a Whatman glassfiber filter. Thefilter is rinsed with 2 ml acetone of 50° C. 6 ml tert. Butyl methylether (TBME) are slowly added at 40° C. to the filtrate. The slightlycloudy solution is allowed to cool and seeded at 25° C. Crystallizationtakes then very slowly place. The mixture is stirred over night at r.t.After 16 h, 12 ml additional TBME are added dropwise. The thicksuspension is stirred further for 2 h at 25° C. and filtered.

The solid is washed with 6 ml TBME/acetone 9/1 v/v and dried for 4 h at50° C. and ca 10 mbar to yield a white powder, m.p. 105-106° C.

Water assay: 4.55% m/m

6g) Potassium 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate

A suspension of 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylaceticacid (15.42 mmoles) in acetone is heated to reflux temperature and allowto stir for 10 min at ca. 55° C. The resulting solution is slightlycooled to 50° C. and filtered hot over Whatman glasfiber filter. Thefilter is washed with acetone at 50° C. The filtrate is heated to 50° C.and a mixture of potassium hydroxide 45% (14.65 mmoles) (0.95 eq.) andwater is dropwise added over ca. 15 min. The dropping funnel is rinsedwith water and acetone. The resulting suspension is stirred at 50° C.for 30 min. The slurry is then allowed to cool to 25° C. over ca. 2hours. The suspension is stirred over night at room temperature andfiltered. The filter cake is washed in three portions. The crystals aredried first for 3 h at 50° C./10 mbar and then further for 17 h at 80°C./10 mbar to yield a white powder, m.p. 315-317° C., 326.9° C., meltingenthalpy 29 J/g.

Prinicipal X-ray diffraction peaks: Angle d value 2-Theta ° AngstromIntensity % 6.263 14.10146 100 10.932 8.08664 38.2 12.602 7.01831 24.713.614 6.49915 25.2 14.689 6.02592 22.6 16.669 5.31402 26.9 18.9044.69055 31.7 21.442 4.14078 14.9 21.958 4.04458 17.3 22.829 3.89219 15.724.24 3.66874 22.6 26.114 3.40963 25.8 26.698 3.33632 36.4 26.9883.30112 19.8 28.026 3.1812 33.1 29.173 3.05867 13.8

1. A compound of formula (I)

wherein R is methyl or ethyl; R₃ is halo or C₁-C₆ alkyl; R₄ is C₁-C₆alkyl; R₅ is halo; the above mentioned C₁-C₆ alkyl at R3 and R4 beingoptionally substituted by one or more halo groups; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable estersthereof.
 2. A compound according to claim 1 wherein R₃ is halo.
 3. Acompound according to claim 1 wherein R₄ is methyl or ethyl.
 4. Acompound according to claim 1 wherein R₅ is halo.
 5. A compoundaccording to claim 1 wherein R₃ and R₅ are each independently selectedfrom chloro and fluoro.
 6. A compound according to claim 1 the compoundbeing selected from the following:5-methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid5-ethyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid5-methyl-2-(2′-fluoro-3′-trifluoromethyl-4′-ethylanilino)phenylaceticacid5-ethyl-2-(2′-fluoro-3′-trifluoromethyl-4′-ethylanilino)phenylaceticacid5-methyl-2-(2′-fluoro-3′-trifluoromethyl-4′-methylanilino)phenylaceticacid5-ethyl-2-(2′-fluoro-3′-trifluoromethyl-4′-methylanilino)phenylaceticacid 5-methyl-2-(2′-fluoro-3′-methyl-4′chloroanilino)phenylacetic acid5-ethyl-2-(2′-fluoro-3′-methyl-4′chloroanilino)phenylacetic acid5-methyl-2-(2′-fluoro-3′-ethyl-4′chloroanilino)phenylacetic acid5-ethyl-2-(2′-fluoro-3′-ethyl-4′chloroanilino)phenylacetic acid5-methyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid5-ethyl-2-(2′,4′-dichloro-3′-ethylanilino)phenylacetic acid5-ethyl-2-(2′-fluoro-3′-isopropyl-4′chloroanilino)phenylacetic acid5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic aciddiethylamine salt sodium5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acidtromethamine salt calcium5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate monohydrateLysine 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetatemonohydrate choline5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetate monohydrate.7. A pharmaceutical composition comprising an effective amount of acompound of claim 1 in combination with one or more pharmaceuticallyacceptable carriers.
 8. A method of treating cyclooxygenase-2 (COX-2)dependent disorders in mammals which comprises administering to a mammalin need thereof an effective amount of a compound of claim
 1. 9. Amethod of selectively inhibiting COX-2 activity in a mammal withoutsubstantially inhibiting cyclooxygenase-1 activity which comprisesadministering to a mammal in need thereof an effective COX-2 inhibitingamount of a compound of claim
 1. 10. A method of treating rheumatoidarthritis, osteoarthritis, dysmenorrhea, pain, tumors or inflammation inmammals which comprises administering to a mammal in need thereof acorrespondingly effective amount of a compound of claim
 1. 11. Use of acompound according to claim 1 in the manufacture of a medicament for thetreatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, pain,tumors or inflammation.
 12. A compound according to claim 1 for use inthe treatment of a COX-2 dependent disorder.
 13. A method for thepreparation of a compound of formula (I) of claim 1 which comprises thestep of: (a) coupling a compound of formula (II) or (III)

wherein Z is bromo or iodo; R has meaning as defined above; R_(a) ishydrogen, an alkali metal-cation or lower alkyl, preferably isopropyl;and R₆ and R₇ are lower alkyl; or R₆ and R₇, together with the nitrogenatom, represent morpholino, piperidino or pyrrolidino; with a compoundof formula (IV)

wherein R₃-R₅ have meaning as defined above in the presence of copperand cuprous iodide to obtain a compound of formula (V) or (VI)

and hydrolyzing the resulting compound of formula (V) or (VI) to acompound of formula (I); or (b) condensing a compound of formula (VII)

wherein R₃-R₇ have meaning as defined herein, with a reactive functionalderivative of an acid, e.g., acetic acid, such as acetyl chloride, in aFriedel-Crafts acylation to reaction to obtain, e.g., a compound of theformula (VIII)

wherein R₃-R₇ have meaning as defined herein, which is in turnhydrogenolyzed and then hydrolyzed to obtain a compound of formula (I),wherein R represents, e.g., ethyl; or (c) hydrolyzing a lactam offormula (IX)

wherein R and R₃-R₅ have meaning as defined herein, with a strong base;and in above processes, if desired, temporarily protecting anyinterfering reactive groups and then isolating the resulting compound ofthe invention; and, if desired, converting any resulting compound intoanother compound of the invention; and/or if desired converting a freecarboxylic acid of the invention into a pharmaceutically acceptableester derivative thereof; and/or if desired, converting a resulting freeacid into a salt or a resulting salt into the free acid or into anothersalt.